The overall goal of the research proposed is to develop and validate a quantitative, multi-parametric set of magnetic resonance imaging (MRI) techniques for the assessment of pathological and functional changes accompanying human peripheral neuropathy in vivo. Quantitative MRI metrics of diffusion (primarily sensitive to axonal structure), magnetization transfer (primarily sensitive to myelin), and multiexponential T2 (primarily sensitive to water compartment sizes) have provided valuable information on tissue microstructure and pathological changes in the brain. However, no studies have applied these methods to study peripheral neuropathies in humans in vivo. This can be attributed to the technical challenges associated with MRI of peripheral nerves, including the need for higher spatial resolution, a lack of contrast on standard anatomical images, and the influence of surrounding fat. We propose to address these technical challenges with a program of innovative, technical developments that will provide a set of multiple MRI parameters for characterizing peripheral nerves that in turn will be evaluated as potential biomarkers of nerve pathology. More specifically, the research proposed would focus on development and validation of robust, clinically feasible, high-resolution, quantitative MRI methods (diffusion, MT, MET2) of tibial (from ankle to knee) and sciatic nerves (from knee to hip) to access the length dependent nature of certain neuropathies. As an initial application, the developed methods will be applied in patients with Charcot-Marie-Tooth disease, a slowly progressing group of inherited neuropathies with well-defined genetic causes. Clinically, CMT is divided on the basis of nerve conduction studies (NCS) into CMT1 (primary demyelination with secondary axonal degeneration) and CMT2 (primary axonal degeneration). Our initial studies will assess the ability of quantitative MRI to detect and distinguish pathology in and between CMT subtypes. For validation, correlations between MRI metrics and clinical measures that report of pathological (NCS, skin biopsy) and functional (neuropathy disability score) changes in CMT patients will also be determined. If successful, these studies may yield biomarkers of treatment responses and tissue status for use in clinical trials and drug discovery. Additionally, the developed methods may have broader implications in a number of other peripheral neuropathies (e.g., diabetic neuropathy) as well as in diseases that affect myelin and/or axons within the central nervous system (e.g., multiple sclerosis).